Starting millions of years ago, the heart developed metabolic and
molecular cardioprotective paths. The concept of metabolic protection
includes the recent successful early provision of
glucose-insulin-potassium (GIK) to patients with acute coronary
syndromes in the ambulance to inhibit high harmful free-fatty acid
levels. Molecular cardioprotective pathways also developed in primeval
times. The 2 major paths are the RISK (Reperfusion Injury Salvage
Kinases) path and the SAFE (Survival Activating Factor Enhancement)
path, on which our group in Cape Town has focused. These paths help to
lessen ischaemic-perfusion damage, and may, hypothetically, also be
activated by intense exercise.

The early cardiac physiologists discovered that depriving the heart
of its blood supply led to an acceleration of glycolysis which could
provide anaerobic energy. Richard Bing (1) in the 1950s used the novel
tool of coronary sinus catheterisation to study the energy sources of
human heart muscle in patients with heart failure. He showed that for
its energy sources the heart uses mostly fatty acids and to a lesser
extent glucose. Circulating free-fatty acids (FFA) could inhibit
myocardial glucose oxidation. (2) In 1962 Sodi-Pallares et al. (3)
launched the concept of metabolic therapy using
glucose-insulin-potassium (GIK) solutions that reduced acute
electrocardiographic signs of ischaemic damage.

The mechanism whereby GIK provides benefit is in part by reducing
the toxic high FFA levels that are found in early acute myocardial
infarction (AMI) as a result of major catecholamine stimulation with
acute adipose tissue lipolysis (Fig. 1). (4,5) In heart failure (HF),
beta-blockade and GIK also reduce circulating FFA, while the newer drugs
trimetazidine and ranolazine act metabolically to improve the condition
of patients with ischaemia or HF. (6)

Metabolic therapy must be given early

Almost all of the prior GIK studies for patients with acute
coronary syndromes (ACS) started infusions far too late after the onset
of symptoms. During the critical first hour, GIK infusions could
potentially reduce major energy depletion. Crucial experimental support
for this concept came from relevant work at the University of Cape Town
(UCT) supported by the Chris Barnard Fund, (7) thus supporting the
rationale for the positive IMMEDIATE study in which GIK was infused by
paramedics to patients in the prehospital emergency ambulance setting.
(8) Started immediately after the onset of symptoms, and continued
thereafter, GIK reduced by 40% the rate of the combined cardiovascular
endpoint, cutting in-hospital mortality or cardiac arrest by half,
besides reducing infarct size measured at 30 days. (8)

[FIGURE 1 OMITTED]

Molecular cardioprotection

The extraordinary complexity of the molecular protective pathways
must, like the metabolic paths, have evolved millions of years ago when
rapid cardioprotection was required after the hyperadrenergic stresses
and blood losses experienced when hunting and escaping from wild
animals. (9)

Today these paths can be brought into action during prompt therapy
for acute coronary occlusion by rapid reperfusion, as in AMI. Although
saving many cells otherwise threatened with ischaemic cell death, rapid
reperfusion kills a significant percentage of cells that could have been
saved by the appropriate intervention. Indeed, the time has come to take
reperfusion injury seriously! (10)

Reperfusion damage, with the sudden return of oxygen and reversal
of tissue pH changes, is inevitable during the optimal therapy of AMI by
prompt percutaneous coronary intervention (PCI). Working on this
problem, the group of Hausenloy and Yellon (10) in London discovered the
RISK (Reperfusion Injury Salvage Kinases) cardioprotective pathway. Of
major interest is that metabolic and molecular protection can go hand in
hand. That concept leads to the proposal that insulin therapy, a
promoter of optimal cardiac metabolic protection, can directly promote
cardiac cell survival during reperfusion. (11)

From the evolutionary point of view it would have been inadequate
to have only one molecular cardioprotective path. Thus another path was
discovered, namely the SAFE (Survival Activating Factor Enhancement)
pathway, that is the focus of our group under Sandrine Lecour. (12) This
path involves cytokine protection by low levels of tumour necrosis
factor-alpha (TNF-[alpha]) acting on a specific series of molecular
events and leading to activation of transcription factor signal
transducer and activator of transcription-3 (STAT-3).

The jump from experiments to clinical certainty

Postconditioning by balloon inflation-reflation

Can the basic laboratory data be clinically applied? In animals
such as the baboon, the major part of myocardial metabolic damage occurs
in the first hour. (7) The first human studies with early intervention
were with ischaemic postconditioning. That means that after coronary
flow had been abruptly restored to the previously ischaemic myocardium
by PCI, the intra-coronary balloon was blown up again to cause temporary
ischaemia. The balloon was then released only to be briefly blown up
again, a procedure repeated for five cycles, thereby causing a very
significant reduction in infarct size as in the basic observations made
by Thibault et al. (13) With late reperfusion, after the crucial first 3
hours, the extent of reperfusion damage can be expected to be slight and
the benefit of therapy aimed at reperfusion damage likewise slight or
totally absent.

Remote conditioning

An even more interesting approach is remote conditioning, whereby
intermittent occlusion-reperfusion of a limb acts at a distance to
reduce cardiac reperfusion damage. First shown in patients with coronary
bypass operations by Yellon's group, the concept has now been
widely extended to involve other organs such as kidney and brain. This
approach has found human application by the simple procedure of pumping
up and down an ordinary blood pressure sphygmomanometer in the ambulance
taking patients to hospital. (14) The primary endpoint was myocardial
salvage index at 30 days after primary PCI, measured, by myocardial
perfusion imaging, as the proportion of the area at risk of cell death
but salvaged by treatment. The area saved from cellular death was about
20-25%. This procedure has no known side-effects and reduced the extent
of the infarcted tissue; benefit was seen even in infarcts sustained by
patients who were very rapidly transferred to the emergency room for
PCI, following the onset of symptoms, by the efficient ambulance service
that Denmark enjoys. The vexing question of how remote ischaemic
conditioning works (cardioprotection at a distance) is still a matter of
dispute; there are arguments for both humoral and nervous mechanisms.

From near-certainty to wishful thinking

Wouldn't it be wonderful if we could imagine that certain
foodstuffs or beverages contain protective agents that promote our
molecular ischaemic pathways? Although this is fanciful, nonetheless
there is a possibility that certain components of wine, namely
resveratrol and melatonin, may protect during reperfusion injury during
the therapy of heart attacks. The impact on myocardial infarct size
after coronary occlusion and reperfusion following administration of red
wine, resveratrol, and melatonin to rats has been examined in our
laboratory. (15) Both resveratrol and melatonin gave substantial
protection. The group of Sandrine Lecour has in the past suggested that
the resveratrol content of red wine may, with only modest intake, reach
blood levels high enough to be cardioprotective although that conclusion
is only inferential and hypothetical. More recently melatonin has been
discovered in red wine and also in white. (15) Melatonin is commonly
used by persons threatened by jet lag during air travel because it
promotes a natural sleep rhythm (and may be one of the reasons why red
wine with meals goes with a good night's sleep).

Speculatively, red wine (16) is part of the French paradox with,
however, many other factors contributing to the relative protection from
myocardial infarction that the French enjoy, because of their
traditional lifestyle (which regretfully is now fading). Overall, modest
wine intake is of itself no panacea but rather only a small part of part
of the healthy five-point lifestyle in which non-smoking and daily
vigorous exercise, for more than 30 minutes, are the two top criteria.
(17) As fully argued in my recent book, Living Longer, Living Better,
(18) intense exercise not only acts by promoting preponderance of the
vagus anti-adrenergic protective nervous system at rest, but also by
stimulating the protective molecular paths.

Acknowledgements. Regretfully limitations of space have required
omission of reference to excellent work by highly respected colleagues.
The fuller text, with references, is available from the author.